Mixtures of isomeric acyloctahydronaphthalenes of generic formulas 1, often containing minor concentrations of isomers of generic formula 2 and other structural isomers, are commonly obtained by the acid-catalyzed cyclization of corresponding Diels-Alder adducts of generic formula 3. Diels-Alder adducts 3 are obtained by reacting myrcene with appropriately substituted .alpha.,.beta.-unsaturated carbonyl compounds (Scheme 1). The wavy lines in formulas 1 and 2 represent possible positions of the one double bond; R.sup.1 is a hydrogen atom or an alkyl group, R.sup.2 is a hydrogen atom or an alkyl group, R.sup.3 is an alkyl group. ##STR1##
The cyclization of the Diels-Alder adduct 3a, wherein R.sup.1 .dbd.R.sup.2 .dbd.R.sup.3 .dbd.CH.sub.3, is the most important from the practical standpoint. Isomeric mixtures of acetyl octahydronaphthalenes thus obtained (Scheme 1a) are well-known in the prior art as woody-amber and fruity-amber odorants. The compounds 1a, 2a, 3a are generally present as racemic mixtures, although only one enantiomer is shown for each of them in Scheme 1a. Similarly, when only one enantiomer is shown for compounds in other schemes of this document, such compounds are typically present as racemic mixtures. ##STR2##
Odor quality of such mixtures depends on their isomeric composition, which in turn depends on the method used to cyclize the Diels-Alder adduct 3a. However, until now there has been a lack of information on how the cyclization method affects the isomeric composition, and even on the actual composition of the reported isomeric mixtures. Furthermore, information obtained from some sources is questionable.
For example, G. Ohloff in the article "Chemistry of Odoriferous and Flavoring Substances" in the book "Fortschritte der Chemischen Forschung", 1969, Bd.12/2, S.192, disclosed a compound of formula 1a-.alpha. having the double bond at the location shown in the 1a-.alpha. structure in Scheme 2, and indicated that materials of this nature have "resiny odors" like olibanum, with amber type undertones. The article did not give any information on the origin of this material or how it was prepared. ##STR3##
U.S. Pat. Nos. 3,907,321, 3,911,018, and 3,929,677 disclose the cyclization of the Diels-Alder adduct 3a in the presence of Bronsted acids (such as phosphoric and sulfuric acids), preferably in the presence of an inert solvent (toluene). According to these three patents, cyclization of the Diels-Alder adduct 3a in the presence of 85% phosphoric acid in toluene at 70-80.degree. C. gives, after work-up and distillation, an 86.8% yield of a mixture of isomers possessing an amber aroma. GLC analysis of the product showed two major peaks: 93% of 1a-.beta. isomer, and 7% of the 1a-.alpha. isomer (and/or 1a-.gamma. isomer). After isolation by preparative GLC, the 1a-.beta. isomer had a "slight buttery note with a strong woody amber character", and the 1a-.alpha. isomer (and/or 1a-.gamma. isomer)--"weak, low-keyed with a green vegetable character".
U.S. Pat. Nos. 3,907,321, 3,911,018, and 3,929,677 also disclose using Lewis acids as cyclization catalysts, and contain an example wherein the Diels-Alder adduct 3a is cyclized in the presence of boron trifluoride etherate in toluene. However, the patents do not report yield or product composition from the cyclization.
Russian authors (V. M. Andreev et al., "Pischevaya Promyshlennost", 1990, N 11, p.55-56) cyclized the Diels-Alder adduct 3a at 115-120.degree. C. (in toluene) in the presence of small amounts of phosphoric acid. They found that the product (mainly 1a-.beta. isomer), had a tenacious woody-amber odor with a "velvet" nuance. However, the yield of cyclized product was only 63%. The article mentions the formation of an impurity adversely affecting the odor. The authors subsequently identified the impurity as 1,2,4,9,11-pentamethyl-3-oxatetracyclo[6.2.2.0.sup.2,8.0.sup.4,9 ]dodecane--a by-product resulting from the secondary cyclization of the 1a-.beta. isomer (V. M. Andreev et al., Zh. Org. Khim., 1991, V.27(2), pp.413-414 [CA 115:183058].
Japanese Kokai 6[1994]-40,992 gives the following odor gradation for 1a-.alpha., 1a-.beta., and 1a-.gamma. isomers, but contains no evidence that the isomers were isolated, or any indication of how the isomers were characterized, which makes this gradation questionable: EQU 1a-.alpha.&gt;1a-.gamma.&gt;1a-.beta.,
where "&gt;" means "better".
According to this Kokai, cyclization with Amberlyst-15 (an acidic sulfonated ion-exchange resin) gives better results than cyclization using phosphoric, sulfuric, and p-toluenesulfonic acids. However, continuous cyclization with Amberlyst-15, yielded only 82.1% of the product, or almost 5% lower than in the above mentioned U.S. patents using phosphoric acid, and the Kokai gave no information on the concentration of unreacted starting material. Moreover, the example reveals significant difficulties in controlling the conversion of the Diels-Alder adduct 3a and the isomer ratio at the same time. Batch format allowed better control of conversion, and less than 2% of unreacted starting material remained, but the yield was significantly lower (74.2%). Lower yields, difficulties of control in the continuous version, and other disadvantages such as mechanical friability of catalyst and large ratio of catalyst to substrate (0.7) in the batch version, make heterogeneous catalysis by Amberlyst-15 unattractive.
A one-pot version of the Diels-Alder reaction of myrcene and MPO to produce the Diels-Alder adduct 3a, and its subsequent cyclization in the presence of a Lewis acid (not specified) was published in "Chinese Chemical Letters", 1992, Vol.3, N 7, pp.507-510. The main product (1a-.beta. isomer) was purified via its semicarbazone, and its structure was rigorously proven by .sup.1 H and .sup.13 C NMR spectroscopy, including 2D .sup.1 H (H--H COSY) and 2D .sup.13 C (C--H COSY) versions. No odor description was given and no yield reported.
The first publication concerning the synthesis of compounds of generic formula 2a appeared in Bull. Soc. Chim. France, 1959, pp. 601-606 (M. Mousseron-Canet et al.). Recently it was found that the protocol of Mousseron-Canet does not give compounds of generic formula 2a, but instead gives other types of structures (see EP 743297 and U.S. Pat. No. 5,707,961).
The aforementioned EP 743297 and U.S. Pat. No. 5,707,961 disclose compounds of generic formula 4 (as shown in Scheme 3) as odorants, including a mixture of compounds 4-1 and 4-2 (with Me groups trans to one another) with amber-woody and tobacco odor. The mixture of compounds 4-1+4-2 was obtained by the Grignard methylation of citral, dehydration of the Grignard product by iodine into methylmyrcene, and Diels-Alder reaction of methylmyrcene with methyl isopropenyl ketone followed by the cyclization of the adduct. ##STR4##
EP 743297 also mentions that a compound having structure 2a with cis-methyl groups, namely the 2a-.beta. isomer, is practically odorless. EP 743297 states that the 2a-.beta. isomer can be obtained by the acid-catalyzed isomerization of the corresponding 2a-.gamma. isomer (Scheme 4). EP 743297 does not give the procedure for the isomerization or give spectral data to confirm the structure. ##STR5##
A sophisticated multi-step synthesis of the 2a-.gamma. isomer from .alpha.-ionone according to the Scheme 5 below was disclosed in EP 464357, and U.S. Pat. Nos. 5,180,709, and 5,214, 160. ##STR6##
According to this method, .alpha.-ionone is transformed into methyldihydroionone 5 by reaction with dimethyl CuLi. Next, methyldihydroionone 5 is converted into ester 6 by the haloform reaction and esterification. Ester 6 is reacted with NaOCl, and then ozonized and treated with Zn/H.sub.2 O to give ketoester 7. The latter is converted into lactone 8 by addition of acetylene-MgBr (with spontaneous cyclization) followed by partial hydrogenation of the triple bond. After introduction of a methyl group by LDA/MeI, the product is silylated (BuLi/Me.sub.3 SiCl), isomerized (reflux in toluene; Ireland-Claisen rearrangement) and methylated again (MeLi/ether) to give the 2a-.gamma. isomer. The structure of the 2a-.gamma. isomer was proven on the basis of its NMR spectra.
These patents state that the 2a-.gamma. isomer possesses a very powerful amber woody odor, with an enormously low odor threshold value (5 pg/l air) compared to the 1a-.beta. isomer, which has a threshold value of 500 ng/l (100,000 times). In "Perfumes. Art, Science, Technology" [P. M. Muller and D. Lamparsky, eds. Blackie Academic & Professional, London-New-York-Tokyo-Melbourne-Madras, 1994, p.197] the 2a-.gamma. isomer was also mentioned as having a powerful woody amber-like note with an odor threshold of about 3 pg/l.
Finally, it was found that the 2a-.gamma. isomer appears as a "minor side product" in the acid catalyzed cyclization of Diels-Alder adduct 3a of myrcene and (E)-3-methylpent-3-en-2-one (MPO) [G. Frater et al. 213th ACS National Meeting San-Francisco, Calif., Apr. 13-17, 1997. Books of Abstracts, Part 2, p.147].
There is even less information regarding the cyclization of Diels-Alder adducts of generic formula 3 other than 3a. British Pat. No. 896,039 claims a method of producing derivatives of octahydronaphthalene wherein a compound of the general formula: ##STR7## in which R.sup.2, R.sup.3, and R.sup.4 are hydrogen atoms, or alkyl groups, and in which R.sup.1 is a hydroxy, alkyl, or alkoxy group, or in which R.sup.1 is a hydrogen atom and the compound is in the form of a Schiff base, is cyclized with phosphoric acid, or boron trifluoride, or mixtures thereof, at a temperature between -30.degree. C. and +75.degree. C., or is cyclized with sulfuric acid or formic acid, or mixtures thereof, at a temperature between -30.degree. C. and +10.degree. C. The patent does not contain examples which could be considered in conjunction with the present document.
Cyclization of the Diels-Alder adduct 3b (R.sup.1 .dbd.R.sup.2 .dbd.H; R.sup.3 .dbd.Me) in the form of its Shiff's base was described in G. Ohloff, Liebigs Annalen der Chemie, 1957, Bd. 606, S. 100-123 (see pages 112 and 116), and also in U.S. Pat. No. 2,933,506, wherein the Shiff base was cyclized at -15.degree. C. in the presence of a large excess of 62% sulfuric acid. ##STR8##
Cyclization of the Diels-Alder adducts 3c (R.sup.1 .dbd.Et; R.sup.2 .dbd.H; R.sup.3 .dbd.Me) and 3d (R.sup.1 .dbd.H; R.sup.2 .dbd.Me; R.sup.3 .dbd.Et), was mentioned in U.S. Pat. Nos. 3,911,018 and 3,929,677 as giving respectively products with "green, buttery, woody", and "fruity, woody, pineapple-like and ionone-like" odors. According to these U.S. patents, the cyclization was conducted using the procedure given in British patent no. 896,039. However, the U.S. Pat. Nos. 3,911,018 and 3,929,677 did not give information on the yields and details of the procedure. ##STR9## Thus, it is known that: 1. Mixtures of isometric acetyloctahydronaphthalenes obtained by the acid-catalyzed cyclization of the Diels-Alder adduct 3a contain 1a-.beta. isomer as the major constituent, and the 2a-.gamma. isomer as a minor side product. Available information on the odor, presence, structures and concentrations of other constituents is insufficient;
2. Odor strength and odor quality of such mixtures may depend largely on the concentration of the minor 2a-.gamma. side product because of its enormously low odor threshold (3-5 pg/l vs. 500 ng/l for the major 1a-.beta. isomer); and PA1 3. Cyclization by-product 1,2,4,9,11-pentamethyl-3-oxatetracyclo[6.2.2.0.sup.2,8.0.sup.4,9 ]-dodecane (POD) adversely affects the odor of such mixtures. PA1 a. formulas 1, 2, and 3 are as shown below: ##STR10## b. one of the wavy lines in each of formulas 1 and 2 represents a double bond, and the two other wavy lines represent a single bond; PA1 c. R is a linear or cyclic alkyl group, or hydroxyalkyl group, or alkoxyalkyl group, or aryl group, and is substituted or unsubstituted, saturated or unsaturated; PA1 d. R.sup.1 and R.sup.2 are independently hydrogen or lower alkyl; PA1 e. R.sup.3 is lower alkyl; and PA1 f. the configuration at carbon b and c in formula 1, and a and b in formula 2, is independently R or S. PA1 a. formulas 1, 2, and 12 are as shown below: ##STR11## b. one of the wavy lines in each of formulas 1 and 2 represents a double bond, and the two other wavy lines represent a single bond; PA1 c. R is a linear or cyclic alkyl group, or hydroxyalkyl group, or alkoxyalkyl group, or aryl group, and is substituted or unsubstituted, saturated or unsaturated; PA1 d. R.sup.1 and R.sup.2 are independently hydrogen or lower alkyl; PA1 e. R.sup.3 is lower alkyl; PA1 f. the configurations at carbon b and c in structures 1 and 12, and a and b in structure 2 are independently R or S. PA1 a. formulas 1, 2, and 3 are as shown below in Scheme 6: ##STR12## b. one of the wavy lines in each of formulas 1 and 2 represents a double bond, and the two other wavy lines represent a single bond; PA1 c. R is a substituted or unsubstituted, saturated or unsaturated, linear or cyclic alkyl group, or hydroxyalkyl group, or alkoxyalkyl group, or aryl group; PA1 d. R.sup.1 and R.sup.2 are independently hydrogen or lower alkyl; PA1 e. R.sup.3 is lower alkyl; and PA1 f. the configurations at carbons b and c in structure 1 and a and b in structure 2 are independently R or S. PA1 a. formulas 1, 2, and 12 are as shown below: ##STR14## b. one of the wavy lines in each of formulas 1 and 2 represents a double bond, and the two other wavy lines represent a single bond; PA1 c. R is a linear or cyclic alkyl group, or hydroxyalkyl group, or alkoxyalkyl group, or aryl group, and is substituted or unsubstituted, saturated or unsaturated; PA1 d. R.sup.1 and R.sup.2 are independently hydrogen or lower alkyl; PA1 e. R.sup.3 is lower alkyl; PA1 f. the configurations at carbon b and c in structures 1 and 12, and a and b in structure 2 are independently R or S.